Bio-Responsive and Immune Protein-Based Therapies for Inhibition of Proteolytic Enzymes in Dental Tissues

用于抑制牙齿组织中蛋白水解酶的基于生物响应和免疫蛋白的疗法

基本信息

批准号：
10555093
负责人：
Ana Paula Piovezan Fugolin
金额：
$ 66.13万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-17 至 2028-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555093
关键词：
Address Adhesives Amino Acid Sequence Animal Model Antibodies Bacteria Binding Biochemistry Biocompatible Materials Biodegradation Biology Biotechnology Chemicals Clinical Collagen Complex Dental Dental Restoration Failure Dental caries Dentin Dentistry Development Diffusion Disease Drug Delivery Systems Employment Encapsulated Enzyme Inhibition Enzyme Inhibitor Drugs Enzymes Epigallocatechin Gallate Extracellular Matrix Formulation Gel Gelatinases Generations Goals Heart Diseases Human body Hydrogels Immune Immunology Infiltration Llama Maintenance Malignant Neoplasms Matrix Metalloproteinases Mediating Medical Medicine Metalloproteases Micelles Morphogenesis Mucous Membrane National Institute of Dental and Craniofacial Research Oral health Organ Pathogenicity Pathologic Pathway interactions Patient Care Peptide Hydrolases Peptides Periodontal Diseases Periodontal Pocket Periodontitis Pharmaceutical Preparations Physiological Play Polymers Procedures Process Proteins Public Health Quercetin Recurrence Research Research Personnel Role Rupture Sepsis Specificity System Techniques Technology Therapeutic Therapeutic Agents Time Tissue Engineering Tissue Preservation Tissues Tooth Extraction Tooth Loss Tooth structure Translating Translations United States Vulnerable Populations Water alveolar bone clinical care collagenase cytokine delivery vehicle dental adhesive dental structure design design verification efficacy evaluation experimental study forging functional group immunoregulation improved inhibitor innovation materials science metastatic colorectal microbial multidisciplinary nanobodies nanomicelles nanomolar nanoparticle oral condition oral tissue particle polyphenol preservation prevent repaired restorative material screening skills stem tissue regeneration tool treatment strategy tumor

项目摘要

SUMMARY This multidisciplinary proposal translates the efforts of a highly skilled group of researchers forging unprecedented pathways to promote hard and soft dental tissues preservation. Cutting-edge strategies inspired in approaches used in the medical field are employed to inhibit selectively endogenous metalloproteinases responsible for mediating the degradation of the collagen. In Dentistry, the destruction of this essential component of the extracellular matrix is strongly associated with the progression of periodontal disease and the breakdown of the dental substrate/restorative material interface leading to bacteria recolonization and recurrent caries, the primary cause of failure of dental restorations. These pathological conditions together are responsible for almost 80% of the tooth extractions in the United States. In order to address this serious public health issue, two innovative platforms are proposed. The first strategy is based on the encapsulation of two potent MMP inhibitors, the polyphenols quercetin and epigallocatechin gallate, in nano micelles cleavable by MMPs. The shell of the particles is composed of peptides with specific sequences of amino acids recognized and cleaved by the targeted MMPs, leading to rupture of the micelles and the release of the inhibitor molecules. In essence, this system enables the MMP to inhibit itself. The second strategy is an immunomodulatory platform based on the introduction of anti-MMP nanobodies, single domain antibodies derived from llama heavy-chain only antibodies, to inhibit/cease MMP proteolytic activity. As nanoparticles or nanobodies delivery vehicles, a dental primer formulation and a newly-designed multifunctional hydrogel are used for the adhesive interface and periodontal pockets, respectively. To validate the designed platforms, tooth-on-a-chip and animal models are being added in order to fast-track their translation into clinical care. The innovation of this proposal stems from: (1) the employment of a pioneering approach to inactivate MMPs in dental tissues based on enzymatic-responsive nanoparticles to deliver inhibitors, and (2) the introduction of a new paradigm based on the modulation of the MMPs activity by nanobody technology. After completing this project, we will have these two platforms tailored and validated to be delivered in vehicles compatible with the current clinical techniques employed to treat periodontitis and to hybridize the dentin during the restorative procedures, which will allow to bridge the gap between cutting-edge research and improved patient care. In addition, these platforms can be either combined or tailored in more complex and multi-functional entities and programmed to respond to a variety of enzymes and cytokines, which provides new opportunities to develop innovative dental tissue regeneration/preservation therapeutics to minimize tooth loss especially in highly vulnerable population.

概括这项多学科的建议翻译了一群熟练的研究人员的努力，锻造了前所未有的促进坚硬和软牙科组织保存的途径。启发使用的尖端策略使用医疗领域来抑制负责介导的内源性金属蛋白酶胶原蛋白的降解。在牙科中，细胞外基质的这一重要组成部分的破坏是强烈的与牙周疾病的进展以及牙科基质/修复材料的分解有关界面导致细菌再殖民化和复发性龋齿，这是牙齿修复的失败的主要原因。这些病理状况在一起是美国近80％的牙齿提取。为了解决这个严重的公共卫生问题，提出了两个创新的平台。第一个策略是基于在纳米胶束中封装了两个有效的MMP抑制剂，多酚槲皮素和epigallocatechin Gallate MMP可裂解。颗粒的外壳由肽的特定序列识别为识别的氨基酸序列并被靶向的MMP裂解，导致胶束破裂和抑制剂分子的释放。在本质，该系统使MMP能够抑制自身。第二种策略是基于引入抗MMP纳米体，单个域抗体，源自拉玛仅重链抗体，抑制/停止MMP MMP蛋白水解活性。作为纳米颗粒或纳米构造的递送车，牙入底漆的配方和新设计的多功能水凝胶分别用于粘合界面和牙周口袋。到为了快速浏览其翻译进入临床护理。该提案的创新源于：（1）使用开创性的方法来失活基于酶 - 响应性纳米颗粒以递送抑制剂的MMP，以及（2）引入A 基于NanoBody技术对MMPS活性的调节的新范式。完成该项目后，我们将对这两个平台进行量身定制和验证，以便在与当前临床的车辆中交付用于治疗牙周炎和在修复程序中杂交牙本质的技术，这将允许弥合尖端研究和改善患者护理之间的差距。此外，这些平台可以是在更复杂和多功能的实体中合并或量身定制，并编程以响应各种酶和细胞因子，它为开发创新的牙科组织再生/保存提供了新的机会治疗方法可最大程度地减少牙齿脱落，尤其是在高度脆弱的人群中。